Results from a multi-center, randomized, double-blind, double dummy, parallel group clinical trial which enrolled 881 patients with heart failure (HF) with reduced ejection fraction (HFrEF-left ventricular ejection fraction of 40% or less) have shown superior efficacy of Sacubitril–Valsartan combination (Entresto; Novartis) in reducing N-terminal pro-B-type natriuretic peptide compared to Enalapril alone. The patients were hospitalized for acute decompensation of HF, and treatment with Sacubitril–Valsartan achieved a greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations without any significant offsetting serious adverse events. Findings from the trial were presented at the 2018 AHA Scientific Session and simultaneously published in the New England Journal of Medicine (NEJM).
The PIONEER-HF trial enrolled patients from 129 different sites across the United States and randomized in a 1:1 fashion to either receive Sacubitril–Valsartan (target dose, 97 mg of Sacubitril with 103 mg of Valsartan twice daily) or Enalapril (target dose, 10 mg twice daily). In addition to including patients hospitalized for acute decompensated heart failure with reduced ejection fraction (medically stabilized), the PIONEER-HF also included patients with newly diagnosed HF, patients without prior history of exposure to high doses of guideline-directed medications for heart failure, and patients not receiving conventional renin-angiotensin system inhibitors at the time of randomization. The inclusion of such a diverse patient population enabled the investigators to bridge the gaps that were not addressed in previous studies (such as the PARADIGM trial, which enrolled only ambulatory outpatients).
During the 8-week trial period, the investigators found that the ratio of the geometric mean of NT-Pro BNP values obtained at weeks 4 and 8 to the baseline value (concentration of 1600 pg per milliliter or more) was lower (0.53) in the Sacubitril–Valsartan group as compared with the Enalapril group (0.75) (Percent change, −46.7% vs. −25.3%; Ratio of change with sacubitril–valsartan vs. enalapril = 0.71; 95% confidence interval [CI] = 0.63-0.81; P <0.001). The primary analysis was performed using an analysis of covariance model (ANCOVA) to achieve greater power. Interestingly, the benefit derived from the Sacubitril–Valsartan combination in the form of greater reduction in NT-Pro BNP compared to Enalapril alone was also accompanied by a reduction in the concentration of high-sensitivity cardiac troponin T (a biomarker of myocardial injury; Ratio of change with Sacubitril–Valsartan vs. Enalapril = 0.85, 95%CI = 0.77-0.94). The superior efficacy achieved via the Sacubitril-Valsartan combination was not accompanied by any significant serious adverse side effects such as worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema.
“The favorable effect of Sacubitril–Valsartan, as compared with Enalapril, was evident from the in-hospital initiation of treatment and continued to be present during the transition to home and throughout the subsequent “vulnerable period,” during which morbidity and mortality among patients with acute decompensated heart failure remain high.”
The limitations of the trial include a prolonged in-hospital stay of the patients due to the administration of placebo alone for the first two dosages in the Sacubitril–Valsartan group followed by mandatory observation for 6 hours after the third dose. In addition, approximately 0.5% of the patients were lost to follow-up and 15% had missing data on the NT-proBNP concentration. Despite these limitations, the superior efficacy of Sacubitril–Valsartan compared to Enalapril in achieving lower NT-proBNP levels remained significant at the end of the trial period.